Development & Activation of T Lymphocytes

Lecture 11

Methods of cell death

Apoptosis/PCD & Necrosis

PCD

Programmed cell death

What triggers apoptosis/PCD?

Specific signal

What triggers necrosis?

Injury

What occurs during apoptosis/PCD?

• Condensation of chromatin

• Collapse of nucleus

• Aggregation of cytoplasmic organelles

• Loss of cytoplasmic volume

• Blebbing of cell membrane

Does apoptosis/PCD stimulate inflammatory response?

No

Results of apoptosis/PCD

• Removal of aging cells

• Clearing of differentiated or activated cells at end of life span

• Destruction of self-reacting B- & T-cells during development

Does necrosis stimulate inflammatory response?

Yes (strong inflammatory response)

Results of necrosis

Tissue damage

Development & maturation of T lymphocytes occurs in the ______

thymus

Why doesn’t involution of the thymus impact T cell numbers & immunity in adults?

T cells are long-lived & self-renewing

_____________ enter the thymus and develop into mature T cells.

Bone marrow derived progenitor cells

What types of mature T cells develop in the thymus?

CD4+ T cells, CD8+ T cells, & γδT cells

What marks each developmental stage of T cell development in the thymus?

Changes in protein expression & rearrangement in TCR gene loci

Progenitor cells are also known as…

thymocytes

In the thymus, more than ____ of the progenitor cells die during development

95%

Progenitor cells enter the thymus from the ____

blood

After entering the thymus, progenitor cells migrate to the ________.

subscapular region

What functions do not occur while progenitor cells are in the subscapular region?

Expression of CD4 & CD8 (double negative) & rearrangement of TCR genes

Where do progenitor cells migrate to from the subscapular region?

Cortex & medulla

Successful rearrangement & expression of γ and δ genes result in…

Development of mature γδT cells, which leave the thymus

Successful rearrangement and expression of α and β chains lead to…

Development of mature αβT cells, which express both CD4 and CD8 co-receptors (double-positive)

Double positive T cells undergo 2 stages of the selection process:

1. Positive selection

2. Negative selection

Where does positive selection occur?

Cortex of the thymus

What occurs during positive selection?

Double positive thymocytes interact with self-MHC I & II molecules expressed on the cortical epithelium, and will proliferate if able to interact or die via apoptosis if unable

What happens to thymocytes that interact with MHC I molecules in positive selection?

They will lose expression of CD4 & become CD8+ T cells

What happens to thymocytes that interact with MHC II molecules in positive selection?

They will lose expression of CD8 & become CD4+ T cells

Where does negative selection occur?

Thymic medulla at the cortico-medullary junction

What occurs during negative selection?

The single-positive thymocytes interact with MHC I or II molecules expressed by dendritic cells, and will die via apoptosis if they interact tightly with MHC I or II

Function of apoptosis in negative selection

Clonal deletion and production of self-tolerant T cells

Clonal deletion

Elimination of self-reactive T cells

Central tolerance

Tolerance of self cells generated through clonal deletion

AIRE

Autoimmune regulator

What is AIRE

Transcription factor that causes expression of small amounts of several tissue-specific proteins (ex: insulin)

Function of AIRE

Allows elimination of T cells that are reactive to peripheral tissue-specific antigens during negative selection

Where are AIREs expressed in negative selection?

Thymic medullary epithelial cells, dendritic cells, & macrophages

What is the end result of negative selection?

Mature CD4+ or CD8+ T cells